Meaningful weight reduction in obesity is difficult to achieve and sustain, and available therapies have significant limitations. Oxytocin (OXT), a hypothalamic hormone that regulates food intake and energy metabolism, is an exciting potential novel therapeutic in obesity management. A small study of obese adults demonstrated weight loss of nearly 20 lbs with 8 weeks of intranasal (IN) OXT at the proposed dose. Data in rodent and nonhuman primate models indicate that OXT drives weight loss by (1) increasing energy expenditure, (2) inducing lipolysis, and (3) reducing food consumption. We propose a randomized, placebo- controlled study of sustained IN OXT to determine whether OXT reduces body weight, increases energy expenditure and reduces total, visceral and liver fat in obese humans, as it does in animal models. We will also characterize the effects of sustained OXT on caloric intake and relevant neural pathways using cutting-edge neuroendocrine, neuroimaging, and behavioral measures. In a study of 60 obese men and women, we hypothesize that eight weeks of IN OXT (24 IU qid) compared to placebo will result in (a) weight loss, (b) increased resting energy expenditure; and (c) reduced total body, visceral and liver fat. Building on our prior findings indicating that OXT may achieve weight reduction in part by modulating reward and impulse control neural pathways to curb eating, we further hypothesize that OXT will result in reduced caloric intake at a test meal, independent of change in weight, compared to placebo, mediated by (a) reduced fasting and post- prandial fMRI activation of reward-related food motivation brain regions (ventral tegmental area, basal ganglia) using a visual food stimuli paradigm; and (b) increased impulse control accompanied by increased fMRI activation and functional connectivity of impulse control brain regions (anterior cingulate, dorsolateral prefrontal cortex) during a validated task requiring the engagement of impulse control to suppress impulsive responses. This study will demonstrate the efficacy and increase our understanding of the underlying mechanisms of IN OXT as a potential weight loss drug -- critical steps in the translation of preclinical findings to humans and optimizing therapies for patients with obesity.